Randomized trial of inhaled nitric oxide to treat acute pulmonary embolism: The iNOPE trial

BACKGROUND: The study hypothesis is that administration of inhaled nitric oxide (NO) plus oxygen to subjects with submassive pulmonary embolism (PE) will improve right ventricular (RV) systolic function and reduce RV strain and necrosis, while improving patient dyspnea, more than treatment with oxygen alone. METHODS: This article describes the rationale and protocol for a registered (NCT01939301), nearly completed phase II, 3-center, randomized, double-blind, controlled trial. Eligible patients have pulmonary imaging-proven acute PE. Subjects must be normotensive, and have RV dysfunction on echocardiography or elevated troponin or brain natriuretic peptide and no fibrinolytics. Subjects receive NO plus oxygen or placebo for 24 hours (±3 hours) with blood sampling before and after treatment, and mandatory echocardiography and high-sensitivity troponin posttreatment to assess the composite primary end point. The sample size of N=78 was predicated on 30% more NO-treated patients having a normal high-sensitivity troponin (<14 pg/mL) and a normal RV on echocardiography at 24 hours with α=.05 and β=.20. Safety was ensured by continuous spectrophotometric monitoring of percentage of methemoglobinemia and a predefined protocol to respond to emergent changes in condition. Blinding was ensured by identical tanks, software, and physical shielding of the device display and query of the clinical care team to assess blinding efficacy. RESULTS: We have enrolled 78 patients over a 31-month period. No patient has been withdrawn as a result of a safety concern, and no patient has had a serious adverse event related to NO. CONCLUSIONS: We present methods and a protocol for the first double-blinded, randomized trial of inhaled NO to treat PE

Inhaled nitric oxide to treat intermediate risk pulmonary embolism: A multicenter randomized controlled trial

Objective To test the hypothesis that adjunctive inhaled NO would improve RV function and viability in acute PE. Methods This was a randomized, placebo-controlled, double blind trial conducted at four academic hospitals. Eligible patients had acute PE without systemic arterial hypotension but had RV dysfunction and a treatment plan of standard anticoagulation. Subjects received either oxygen plus 50 parts per million nitrogen (placebo) or oxygen plus 50 ppm NO for 24 h. The primary composite endpoint required a normal RV on echocardiography and a plasma troponin T concentration <14 pg/mL. The secondary endpoint required a blood brain natriuretic peptide concentration <90 pg/mL and a Borg dyspnea score ≤ 2. The sample size of N = 76 tested if 30% more patients treated with NO would achieve the primary endpoint with 80% power and alpha = 5%. Results We randomized 78 patients and after two withdrawals, 38 were treated per protocol in each group. Patients were well matched for baseline conditions. At 24 h, 5/38 (13%) of patients treated with placebo and 9/38 (24%) of patients treated with NO reached the primary endpoint (P = 0.375). The secondary endpoint was reached in 34% with placebo and 13% of the NO (P = 0.11). In a pre-planned post-hoc analysis, we examined how many patients with RV hypokinesis or dilation at enrollment resolved these abnormalities; 29% more patients treated with NO resolved both abnormalities at 24 h (P = 0.010, Cochrane's Q test). Conclusions In patients with severe submassive PE, inhaled nitric oxide failed to increase the proportion of patients with a normal troponin and echocardiogram but increased the probability of eliminating RV hypokinesis and dilation on echocardiography

Evaluation of the pulmonary embolism rule out criteria (PERC rule) in children evaluated for suspected pulmonary embolism

Background The pulmonary embolism rule out criteria (PERC) reliably predicts a low probability of PE in adults. We examine the diagnostic accuracy of the objective components of the PERC rule in children previously tested for PE. Methods Children aged 5–17 who had a D-dimer or pulmonary vascular imaging ordered from 2004 to 2014 in a large multicenter hospital network were identified by query of administrative databases. Using explicit, predefined methods, trained abstracters selected charts of children clearly tested for PE, collected the 8 objective variables for PERC, and determined PE criterion standard status (image or autopsy confirmed PE or deep vein thrombosis within 30 days by query of the Indiana Network for Patient Care (INPC)). Results We identified 543 patients, including 56 (10.3%, 95% CI: 7.8–13.1%) who were PE+, with a mean and median age of 15 years. All 8 objective criteria from PERC were negative in 170 patients (31%), including one with PE (false negative rate 0.6%, 0–3.2%). Diagnostic sensitivity and specificity were 98.2% (90.5–100%), and 34.7 (30.5–39.1%), respectively, leading to a likelihood ratio negative = 0.05 (0.1–0.27). When treated as a diagnostic test based upon sum of criteria positive, PERC had good discrimination between PE+ vs PE− with an area under receiver operating characteristic curve 0.81 (0.75–0.86). Conclusions In this sample of children and teenagers with suspected PE, the PERC rule was negative in 31%, and demonstrated good overall diagnostic accuracy, including a low false negative rate. These data support the need for a large, prospective diagnostic validation study of PERC in children

Impact of Patient Affect on Physician Estimate of Probability of Serious Illness and Test Ordering

Purpose The authors hypothesize patient facial affect may influence clinician pretest probability (PTP) estimate of cardiopulmonary emergency (CPE) and desire to order a computerized tomographic pulmonary angiogram (CTPA). Method This prospective study was conducted at three Indiana University–affiliated hospitals in two parts: collecting videos of patients undergoing CTPA for suspected acute pulmonary embolism watching a humorous video (August 2014–April 2015) and presenting the medical histories and videos to clinicians to determine the impact of patient facial affect on physicians’ PTP estimate of CPE and desire to order a CTPA (June–November 2015). Patient outcomes were adjudicated as CPE+ or CPE− by three independent reviewers. Physicians completed a standardized test of facial affect recognition, read standardized medical histories, then viewed videos of the patients’ faces. Clinicians marked their PTP estimate of CPE and desire for a CTPA before and after seeing the video on a visual analog scale (VAS). Results Fifty physicians completed all 73 videos. Seeing the patient’s face produced a > 10% absolute change in PTP estimate of CPE in 1,204/3,650 (33%) cases and desire for a CTPA in 1,095/3,650 (30%) cases. The mean area under the receiver operating characteristic curve for CPE estimate was 0.55 ± 0.15, and the change in CPE VAS was negatively correlated with physicians’ standardized test scores (r = −0.23). Conclusions Clinicians may use patients’ faces to make clinically important inferences about presence of serious illness and need for diagnostic testing. However, these inferences may fail to align with actual patient outcomes

Settling down without settling: Perceived changes in partner preferences in response to COVID-19 concern

The goal of this study was to explore the positive association between concern related to COVID-19 and single individuals’ perceived changes to their partner preferences. In addition, we investigated the mediating role of fear of being single. Results indicated that people with greater COVID-19 concern perceived an increase in the importance of stability, family commitment, and physical/social attractiveness, as well as fear of being single. Fear of being single only negatively predicted the importance of physical/social attractiveness, whereas it positively predicted the importance of stability and family commitment. Thus, in most cases, people with a greater concern for COVID-19 perceived themselves to become more selective, even when they exhibit higher levels of fear of being single

Cross-sectional characterization of HIV-1 env compartmentalization in cerebrospinal fluid over the full disease course

To characterize HIV-1 env compartmentalization between cerebrospinal fluid (CSF) and peripheral blood plasma over all stages of the HIV-1 disease course, and to determine the relationship between the extent of CSF HIV-1 env compartmentalization and clinical neurologic disease status

Perception of Physician Empathy Varies With Educational Level and Gender of Patients Undergoing Low-Yield Computerized Tomographic Imaging

Objective: Lack of empathic communication between providers and patients may contribute to low value diagnostic testing in emergency care. Accordingly, we measured the perception of physician empathy and trust in patients undergoing low-value computed tomography (CT) in the emergency department (ED). Methods: Multicenter study of ED patients undergoing CT scanning, acknowledged by ordering physicians as unlikely to show an emergent condition. Near the end of their visit, patients completed the Jefferson Scale of Patient Perception of Physician Empathy (JSPPPE), Trust in Physicians Survey (TIPS), and the Group Based Medical Mistrust Scale (GBMMS). We stratified results by patient demographics including gender, race, and education. Results: We enrolled 305 participants across 9 sites with diverse geographic, racial, and ethnic representation. The median scores (interquartile ranges) for the JSPPPE, TIPS, and GBMMS for all patients were 29 (24-33.5), 55 (47-62), and 18 (12-29). Compared with white patients, nonwhite patients had similar JSPPPE and TIPS scores but had higher (worse) GBMMS scores. Females had significantly lower JSPPPE and TIPS scores than males, and scores were lower (worse) in females with college degrees. Patients in the lowest tier of educational status had the highest (better) JSPPPE and TIPS scores. Scores were invariant with physician characteristics. Conclusion: Among patients undergoing low-value CT scanning in the ED, the degree of patient perception of physician empathy and trust varied based on the patients’ level of education and gender. Given this variation, an intervention to increase patient perception of physician empathy should contain individualized strategies to address these subgroups, rather than a one-size-fits-all approach

Contrasting Genetic Structure in Two Co-Distributed Species of Old World Fruit Bat

The fulvous fruit bat (Rousettus leschenaulti) and the greater short-nosed fruit bat (Cynopterus sphinx) are two abundant and widely co-distributed Old World fruit bats in Southeast and East Asia. The former species forms large colonies in caves while the latter roots in small groups in trees. To test whether these differences in social organization and roosting ecology are associated with contrasting patterns of gene flow, we used mtDNA and nuclear loci to characterize population genetic subdivision and phylogeographic histories in both species sampled from China, Vietnam and India. Our analyses from R. leschenaulti using both types of marker revealed little evidence of genetic structure across the study region. On the other hand, C. sphinx showed significant genetic mtDNA differentiation between the samples from India compared with China and Vietnam, as well as greater structuring of microsatellite genotypes within China. Demographic analyses indicated signatures of past rapid population expansion in both taxa, with more recent demographic growth in C. sphinx. Therefore, the relative genetic homogeneity in R. leschenaulti is unlikely to reflect past events. Instead we suggest that the absence of substructure in R. leschenaulti is a consequence of higher levels of gene flow among colonies, and that greater vagility in this species is an adaptation associated with cave roosting